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HEREDITARY MONOGENIC DISEASES

           

Porphyria

Porphyrias are a group of rare inherited disorders. An important part of hemoglobin, called heme, is not made properly. Heme is also found in myoglobin, a protein found in certain muscles. Normally, the body makes heme in a multi-step process and porphyrins are made during several steps of this process. People with porphyria are lacking certain enzymes needed for this process. This causes abnormal amounts of porphyrins or related chemicals to build up in the body.

Porphyria is inherited through an autosomal dominant process (with the exception of Doss porphyria). This means one parent has to have the disorder for it to be passed down through the family and each child will have a 50% chance of inheriting this hyperactive enzyme.

Porphryias are complex disorders, with different prognosis (at times unpredictable), and have a great variety of symptoms and signs. Nonetheless it is important to note that the great majority of carriers of this genetic defect can be asymptomatic their whole life.

There are many different forms of porphyria. The most common type is porphyria cutanea tarda (PCT).

Porphyria Cutanea Tarda (PCT)

This disease is the most common of the porphyrias and results from a deficiency of the enzyme uroporphyrinogen decarboxylase (UROD).

There are familiar and sporadic forms of the disorder, being the sporadic the most frequent (around 80% of the cases). In it, the enzyme hyperactivity stays on the liver tissue and may reach normal values once the disorder is in remission. There is not a familial affectation. The origin of sporadic porphyria is unknown but it is suggested that alcohol, iron overload and hepatic viruses inactivate the enzyme in those individuals with the defect.

Familial PCT is also an autosomal dominant disease.

A form of toxic or environmental PCT can also be triggered by halogenated aromatic hydrocarbons, some of which can cause porphyria in laboratory animals as well as in humans.

In Spain, PCT is the most frequent form of porphyria (1.24 cases of 1000 in Madrid).

The overproduction and accumulation of prophyrins is detected in the plasma, urine and liver. This build-up is the cause of the skin symptoms: blisters in uncovered areas of the skin, especially on the back of the hands. These form scabs that when they dry and fall off, leave a characteristic hyper- or hypo-pigmented scar. The skin is very fragile to even the smallest traumas and hypertrichosis (over- abundance of hair growth) can also occur. This skin type of porphyria generally appears in individuals over 40 years of age and does not differentiate between sexes, although there are cases of early onset in familial PCT, in toxic PCT and in cases triggered by oral contraconceptive medicines.

PCT hepatic lesions are more dependent on alcohol consumption or a hepatic viral infection than by porphyria itself which makes its prognosis variable. The evolution of the liver disease in PCT contributes to, among other things, siderosis. The iron deficiency inhibits the activity of the enzymatic system, origin of the disorder. Therefore, iron overload alters heme metabolism. The disease can go into remission in some forms and cases when the triggering factors are eliminated.

SYMPTOMS

Porphyria causes three major symptoms:

  • Abdominal pain or cramping (only in some forms of the disease)
  • Sensitivity to light that can cause rashes, blistering, and scarring of the skin (photodermatitis)
  • Problems with the nervous system and muscles (seizures, mental disturbances, nerve damage)

Attacks can occur suddenly. They often start with severe abdominal pain followed by vomiting and constipation. Being out in the sun can cause pain, sensations of heat, blistering, and skin redness and swelling. Blisters heal slowly, often with scarring or skin color changes. The scarring may be disfiguring. Urine may turn red or brown after an attack.

Other symptoms include:

  • Muscle pain
  • Muscle weakness or paralysis
  • Numbness or tingling
  • Pain in the arms or legs
  • Pain in the back
  • Personality changes

Attacks can sometimes be life-threatening, producing:

  • Low blood pressure
  • Severe electrolyte imbalances
  • Shock

RISK FACTORS

The basis for prevention of the disease, and in many cases, a better development, is to be well informed. Avoiding risks is part of the treatment.

Porphyrias are generally hereditary although there are certain risk factors that can trigger the attacks. When exposed to the trigger, your body´s demand for heme production increases. This overwhelms the deficient enzyme, setting in motion a process that causes signs and symptoms. Examples of triggers include:

  • Certain drugs (barbiturates or sulfonamide antibiotics or, less often, birth control pills, or some drugs that affect the mind or behavior, known as psychoactive drugs)
  • Chemicals
  • Dieting or fasting
  • Smoking
  • Physical stress, such as infections or other illnesses
  • Liver disease
  • Emotional stress
  • Alcohol use
  • Menstrual hormones
  • Sun exposure
  • Excess iron in your body

PREVENTION

Knowing the triggering factors of an acute crisis and following the opportune measures help the patients to prevent them, when possible, and help symptomatic carriers not to develop the disease. The basis of prevention for photo sensitive porphyries is to avoid sunlight and to pay attention to skin care.

  • Use of hats, gloves, cotton or linen garments in summer, and dress adequately to protect the more fragile skin
  • For ocular photosensitivity (photophobia), use of special filters for glasses, high quality sunglasses
  • Addition of filters or yellowish plastics on the windows or car windows is helpful as a prophylaxis, especially in Gunter porphyria as well as recommended in other porphyrias and other pertinent cases or circumstances, like for example if the patient works outside, in vehicles, etc.
  • Doing exercise or sports – competitive or not – especially outside, depends on the advice of a medical professional. In those cases, extreme protective measures should be taken.
  • Personal hygiene: use of pH neutral products is recommended
  • Sunscreen creams (the highest protection possible) containing titanium dioxide or zinc oxide which protect from long wave (380-650 mm) radiation should be used during all seasons of the year, although they are not always sufficient in some cases to prevent skin lesions, especially in more severe porphyria.

When there are lesions (blisters, skin cracks and oozing wounds, infected areas), recommendations for home care include:

  • Use of non-adhesive products
  • The development of the skin condition and its treatment should follow the dermatologist’s recommendations
  • Parents and relatives of a child with porphyria play an important role in the disease prevention, providing the child with information about the disease relative to the child’s age to help the child acquire the proper habits for his condition depending on the prophylactic measures.

Genetic counseling can help those persons who want to have children and have a family history of any type of porphyria.

GENE OR REGION STUDIED


  • HMBS